354 - Intravenous Administration of Umbilical Cord-Derived Mesenchymal Stromal Cells Improves Long-Term Lung Mechanics in Neonatal Mice Exposed to Hyperoxia

Publication Number: 1338.354

Takeshi Fujimoto, Nagoya University Graduate School of Medicine, Aichi, Japan; Saitama Medical Center, Saitama Medical University, Saitama, Japan, Kawagoe, Saitama, Japan; Koji Hirohata, Saitama Medical center, Saitama Medical University, Kawagoe, Saitama, Japan; Fumihiko Namba, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan

Background: Preclinical studies utilizing hyperoxia-induced bronchopulmonary dysplasia (BPD) models suggest that mesenchymal stromal cells (MSCs) ameliorate lung injury and improve lung structure. However, evidence for long-term functional improvement remains limited.

Objective: We aimed to investigate whether intravenous MSCs improve the long-term pulmonary function of a newborn mouse model of BPD.

Design/Methods: Newborn mice were exposed to hyperoxia (95% O2) for 72 hours before being returned to room air. During this period, dams were rotated between hyperoxic and normoxic litters every 24 hours. At 96 hours of age, human umbilical cord-derived MSCs (1 × 10^5 cells/30 µL) or an equivalent volume of phosphate-buffered saline (PBS) was injected intravenously. At 8 weeks of age, mice underwent tracheotomy under anesthesia. Then, they were connected to a computer-controlled animal ventilator (flexiVent). Measurements were performed under anesthesia, with no spontaneous breathing. The parameters examined included respiratory system resistance (Rrs), respiratory system elastance (Ers), Newtonian resistance (Rn), tissue damping (G), tissue elastance (H), static compliance (Cst), and hysteresivity (η = G/H). Postprocedure, Fulton's index was also measured. Results were compared among the normoxic (21% O2 + PBS), hyperoxic (95% O2 + PBS), and treatment (95% O2 + MSC) groups. For body weight and Fulton's index, one-way analysis of variance was performed. For the variables (Rrs, Ers, Rn, G, H, Cst, and η), analysis of covariance with body weight as a covariate was conducted. When a significant main effect was found, Tukey's honestly significant difference (HSD) test was used for post-hoc comparisons. All procedures were approved by Institutional Animal Care and Use Committee and Institutional Review Board.

Results: There were no significant differences in body weight among the three groups. Rrs, Ers, H, and Cst showed significant overall effects (P < 0.001), and Tukey's HSD test revealed that the changes induced by hyperoxia were significantly ameliorated by MSCs, restoring the values to levels comparable to those of the control group (see Figure). G also showed significant overall effects (P < 0.05). No significant differences were observed in Rn, η, and Fulton's index. The analyses of plethysmography, histopathology, and gene expression are ongoing.

Conclusion(s): Mice exposed to 95% hyperoxia for 72 hours exhibited significant alterations in lung mechanics at 8 weeks of age. These changes could be improved to levels comparable to the normoxic group by intravenous administration of umbilical cord-derived MSCs.

MSCs Improve Long-Term Lung Mechanics After P0-P3 Hyperoxia, Assessed at P56.
A-F: respiratory system resistance (Rrs), respiratory system elastance (Ers), Newtonian resistance (Rn), tissue damping (G), tissue elastance (H), and static compliance (Cst) in adult mice exposed to 21% oxygen + PBS, 95% oxygen + PBS, or 95% oxygen + MSCs. Data are presented as least squares (LS) means and 95% confidence intervals; n = 15-20 per group. P values are Tukey-adjusted for multiple comparisons: *P < 0.05, **P < 0.01, ***P < 0.001.